US2009281067A1PendingUtilityA1
Nitroxyl progenitor compounds and methods of use
Est. expiryJan 30, 2024(expired)· nominal 20-yr term from priority
A61P 9/04A61P 9/12C07C 291/08A61P 9/00A61P 9/10C07D 209/42A61P 43/00C07D 207/50C07C 247/18C07C 247/16
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Claims
Abstract
Described herein are nitroxyl progenitor compounds, and compositions including, and methods or generating, the compounds thereof, and methods of treating or preventing disease and disease symptoms using the compounds and compositions.
Claims
exact text as granted — not AI-modified1 . A compound of formula (I), or pharmaceutically acceptable salt, solvate or hydrate thereof:
wherein,
each R 1 is H, alkyl, perhaloalkyl, cycloalkyl, cyclyl, aryl, heterocycloalkyl, heterocyclyl, heteroaryl, each optionally substituted with 1-4 groups that are halo, CN, NO 2 , C(O)OH, C(O)OR, haloalkyl, or electron-withdrawing group;
each R 2 is alkyl, perhaloalkyl, cycloalkyl, cyclyl, aryl, heterocycloalkyl, heterocyclyl or heteroaryl, each optionally substituted with 1-4 groups that are halo, CN, NO 2 , C(O)OH, C(O)OR, haloalkyl, or electron-withdrawing group;
or R 1 and R 2 , together with the nitrogen to which they are both attached, is a heterocycloalkyl, heterocyclyl or heteroaryl ring optionally substituted with one or more groups that are halo, alkyl, C(O)OH, C(O)OR, haloalkyl;
each R is independently alkyl, alkenyl, alkynyl, cycloalkyl, cyclyl, aralkyl, or heteroaralkyl; and
each n and m is independently 0 or 1.
2 . The compound of claim 1 , wherein R 2 is a phenyl substituted with an electron-withdrawing group.
3 . The compound of claim 1 , wherein R 1 is alkyl.
4 . The compound of claim 1 , wherein R 1 is alkyl substituted with C(O)OH.
5 . The compound of claim 1 , wherein R 1 is independently a phenyl substituted with an electron-withdrawing group, and R 2 is independently a phenyl substituted with an electron-withdrawing group.
6 . The compound of claim 1 , wherein R 1 is independently alkyl optionally substituted with an electron-withdrawing group, and R 2 is independently a phenyl substituted with an electron-withdrawing group.
7 . The compound of claim 1 , wherein R 2 is a phenyl with a para-substituent, wherein the para-substituent is an electron-withdrawing group.
8 . The compound of claim 1 , wherein R 1 and R 2 taken together with the nitrogen to which they are both attached, is:
wherein,
X is halo; and
Y is H or halo.
9 . The compound of claim 1 , wherein R 1 is alkyl and R 2 is a phenyl with a para-substituent, wherein the para-substituent is an electron-withdrawing group.
10 . The compound of claim 1 , wherein R 1 is alkyl substituted with C(O)OH and R 2 is a phenyl with a para-substituent, wherein the para-substituent is an electron-withdrawing group.
11 . The compound of claim 1 , wherein both the carbon atom of R 1 attached to the nitroso nitrogen atom and the carbon atom of R 2 attached to the nitroso nitrogen atom are devoid of hydrogen substituents.
12 . The compound of claim 1 , wherein R 1 is independently a phenyl substituted with a 4-carboxy group, and R 2 is independently a phenyl substituted with a 4-carboxy group.
13 . The compound of claim 1 , wherein R 2 is independently a group of formula (III):
wherein,
each U is independently H, alkyl, or an electron-withdrawing group;
each V is independently H or C(O)OH; and
each W is independently an electron-withdrawing group.
14 . The compound of claim 1 , wherein each of R 1 and R 2 is independently a group of formula (III):
wherein,
each U is independently H, alkyl, or an electron-withdrawing group;
each V is independently H or C(O)OH; and
each W is independently an electron-withdrawing group.
15 . The compound of claim 1 , wherein each R 1 is alkyl, cycloalkyl, cyclyl, aryl, heterocycloalkyl, heterocyclyl or heteroaryl, each optionally substituted with 1-4 groups that are halo, CN, NO 2 , C(O)OH, C(O)OR, haloalkyl, or electron-withdrawing group.
16 . The compound of claim 1 , wherein each R 1 is alkyl, cycloalkyl, cyclyl, aryl, heterocycloalkyl, heterocyclyl or heteroaryl, each substituted with 1-4 groups that are halo, CN, NO 2 , C(O)OH, C(O)OR, haloalkyl, or electron-withdrawing group.
17 . A pharmaceutical composition comprising a compound of Formula (I) in claim 1 and a pharmaceutically acceptable carrier.
18 . The composition of claim 17 , further comprising an additional therapeutic agent.
19 . The composition of claim 18 , wherein the additional therapeutic agent is a cardiovascular agent.
20 . The composition of claim 19 , wherein the additional therapeutic agent is a β-antagonist.
21 . A method of treating a subject suffering from or susceptible to a disease or disorder, the method comprising the step of administering to the subject a therapeutic amount of a compound of Formula (I) in claim 1 sufficient to treat the disease or disorder or symptoms thereof under conditions such that the disease or disorder is treated.
22 . The method of claim 21 , wherein the subject is a human.
23 . The method of claim 21 , wherein the subject is a subject identified as being in need of such treatment.
24 . The method of claim 21 , further comprising administering an additional therapeutic agent.
25 . The method of claim 21 , wherein the subject is not suffering from a cancer.
26 . The method of claim 21 , wherein the step of administering the compound comprises administering the compound in a dosage of between about 0.0001 and 4.0 g/day.
27 . The method of claim 21 , wherein the disease, disorder, or symptom thereof is a nitroxyl-mediated disease, disorder, or symptom thereof.
28 . The method of claim 21 , wherein the disease, disorder, or symptom thereof is a cardiovascular disease, disorder, or symptom thereof.
29 . The method of claim 21 , wherein the disease or disorder is heart failure, early-stage chronic heart failure, Class II heart failure, hypertension, coronary obstructions, coronary artery disease (CAD), angina, heart attack, myocardial infarction, cardiac failure, high blood pressure, heart valve disease, or congestive heart failure.
30 . The method of claim 21 , wherein the step of administering comprises administering the compound intravenously or intramuscularly.
31 . A method of administering nitroxyl to a subject comprising the step of administering to the subject a therapeutic amount of a compound of Formula (I) in claim 1 sufficient to provide nitroxyl.
32 . The method of claim 31 , wherein the subject is a subject identified as being in need of such treatment.
33 . A kit comprising an effective amount of a compound of Formula (I) in claim 1 in unit dosage form, together with instructions for administering the compound to a subject suffering from or susceptible to a cardiovascular disease or disorder or symptoms thereof.
34 . The method of claim 21 , further comprising determining a level of Marker in the subject.
35 . The method of claim 21 , wherein the determining of the level of Marker is performed prior to administration of the compound to the subject.
36 . The method of claim 21 , wherein the determining of the level of Marker is performed subsequent to administration of the compound to the subject.
37 . The method of claim 21 , wherein the determining of the level of Marker is performed prior to and subsequent to administration of the compound to the subject.
38 . The method of claim 21 , wherein the levels of Marker performed prior to and subsequent to administration of the compound to the subject are compared.
39 . The method of claim 38 , wherein the comparison of Marker levels is reported by a clinic, laboratory, or hospital agent to a health care professional.
40 . The method of claim 28 , wherein when the level of Marker prior to administration of the compound to the subject is lower than the level of Marker subsequent to administration of the compound to the subject, then the amount of compound administered to the subject is an effective amount.
41 . The method of claim 21 , wherein the compound of Formula (I) in claim 1 is a compound wherein independent R 1 and R 2 groups are those wherein the corresponding protonated amine form of the R 1 R 2 N— moiety has a pKa of about 4.5 or less.
42 . The compound of claim 1 , wherein n and m are both 1.
43 . The compound of claim 1 , wherein n and m are both 0.
44 . The compound of claim 1 , wherein n is 0 and m is 1.
45 . The compound of claim 1 , wherein R 1 and R 2 taken together with the nitrogen to which they are both attached, is any of formulae (IV)-(VII):
wherein,
each U is independently H, alkyl, or an electron-withdrawing group;
each V is independently H or C(O)OH; and
each W is independently an electron-withdrawing group.
46 . The compound of claim 1 that is any of those delineated in Table I.
47 . A method of modulating a target that is phospholamban (PLB), sarcolipin (SLN), cardiac sarco(endo)plasmic reticulum calcium ATP-ase (SERCA2a), skeletal or cardiac sarcoplasmic reticulum (SR), or ryanodine receptors (RyR) in a cell comprising contacting a compound of formula (I) in claim 1 with the cell such that the target is modulated.
48 . A method of modulating a target that is phospholamban (PLB), sarcolipin (SLN), skeletal or cardiac sarco(endo)plasmic reticulum calcium ATPase (SERCA) or isoforms thereof, skeletal or cardiac sarcoplasmic reticulum (SR), or ryanodine receptors (RyR) in a subject comprising administering a compound of formula (I) in claim 1 to the subject such that the target is modulated.
49 . The compound of claim 1 , wherein R 1 is perfluoroalkyl; and m and n are each 0.
50 . The compound of claim 49 , wherein R 1 is CF 3 or CF 2 CF 3 .
51 . The compound of claim 13 , wherein U and V are each H.
52 . The compound of claim 13 , wherein one U is independently an electron-withdrawing group.Join the waitlist — get patent alerts
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